KR20170030494A - Therapeutic agent for keratoconjunctive disorder - Google Patents

Abstract

The present invention provides a therapeutic agent and a prophylactic agent for conjunctival disorder containing saccharin, and is a therapeutic or preventive agent for conjunctival disorder containing saccharin.

Description

{THERAPEUTIC AGENT FOR KERATOCONJUNCTIVE DISORDER}

The present invention relates to a therapeutic agent and a prophylactic agent for conjunctival disorder containing saccharin.

Sacran is known as a polysaccharide derived from freshwater cyanobacteria (Aphanothece sacrum). For the use of saccharin, a polarizing lens, a light trapping agent, a light scattering agent, a flow rate sensor, a play device, an actuator, an adhesive, etc. are expected as a polysaccharide-metal ion hybrid liquid crystal gel. Antioxidant activity, antiallergic activity, and antimicrobial activity have been reported. Therefore, antiviral agents, anticancer agents, food health enhancers, food thickening and stabilizing agents, etc. are expected (for example, Patent Document 1).

For the use of saccharin, a drug delivery system for releasing a drug by using a gel sustained release carrier and its carrier has also been proposed (for example, Patent Document 2).

Sarklan suggests the potential for such a variety of uses, among which it is desirable to explore new medicinal uses.

International Publication WO 2008/062574 A1 Japanese Patent Application Laid-Open No. 2011-68606

In view of the above circumstances, it is an object of the present invention to provide a therapeutic agent and prophylactic agent for conjunctival disorder containing saccharum.

DISCLOSURE OF THE INVENTION The present inventors have found that, in a test for healing efficacy of dry eye and other conjunctival disorders, Sakran exhibits an excellent improvement effect on corneal disorders, and has completed the present invention.

Specifically, the present invention provides the following.

[1] A therapeutic agent or prophylactic agent for each conjunctival disorder containing saccharin.

[2] The therapeutic agent or prophylactic agent according to [1], wherein the conjunctival disorder is at least one selected from the group consisting of keratitis, conjunctivitis, and conjunctivitis.

[3] A group consisting of conjunctival disorder, dry eye, corneal ulcer, corneal erosion, punctate superficial depression, corneal epithelium defect, conjunctival epithelium defect, conjunctival epithelial disorder, dry keratoconjunctivitis, conjunctival keratoconjunctivitis and filiform keratitis Or a pharmaceutically acceptable salt thereof.

[4] The therapeutic agent or prophylactic agent according to any one of [1] to [3], which is an ophthalmic or ophthalmic formulation.

According to the present invention, by containing saccharin, it is possible to provide a therapeutic agent and a prophylactic agent for each conjunctival disorder, which is excellent in water retention and water supply when administered to eyes. Specifically, when the healing efficacy test of the corneal disorder was performed, the saccharum of the present invention exerts an excellent healing stimulation effect in the corneal disorder model, and therefore, the corneal ulcer, corneal erosion, (Conjunctival epithelial disorder), conjunctivitis such as conjunctival epithelium disorder, dry keratoconjunctivitis (dry eye), conjunctival keratoconjunctivitis, and filiform keratitis.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing the segmentation and score of a cornea according to a criterion of a healing efficacy test of a corneal disorder. FIG.

Hereinafter, embodiments of the present invention will be described.

The therapeutic agent and prophylactic agent for each of the conjunctival disorders of the present invention contains saccharin.

Sacchar is a type of sulfated polysaccharide with a molecular weight of 2,000,000 or more and a CAS registration number of 1039552-36-7. Specifically, sacchar means a sugar chain structure in which a sugar structure having a hexose structure and a sugar structure having a pentose structure are linked in a linear or branched chain by an? -Glycoside bond or a? -Glycoside bond Wherein the sugar chain unit comprises lactose-containing sulfated sugar as a saccharide structure, and in the sugar chain unit, 2.7 or more hydroxyl groups per 100 hydroxyl groups are sulfated, or the sulfur element is 1.5 By weight of the sugar derivative.

Sakran is known to be obtained by protonating a polysaccharide extracted from Suizenjori, an endemic strain of Japan, and partially hydrolyzing (for example, Patent Document 1).

The saccharin which can be used in the present invention is not limited to those derived from Suizenjori.

In the present invention, each conjunctival disorder refers to a condition in which the cornea or conjunctiva is damaged by various factors. Each conjunctival disorder may be caused by, for example, leakage of fluid from the dry eye (dry keratoconjunctivitis), as well as by trauma, autoimmune diseases, toxicity to drugs, and the like.

Each conjunctival disorder is largely divided into keratitis such as corneal ulcer, corneal erosion, punctate keratopathy, corneal epithelium defect, conjunctival epithelium defect, conjunctival epithelium disorder, and the like from the viewpoint of pathological condition. Each conjunctival disorder includes keratoconjunctivitis such as dry keratoconjunctivitis, conjunctivitis keratoconjunctivitis and conjunctivitis keratitis from the viewpoint of cause, manifestation site, and illness. The therapeutic agent and prophylactic agent for each conjunctival disorder of the present invention can be used for any conjunctival disorder among these, and is suitable for dry keratoconjunctivitis. Dry conjunctivitis is also known as dry eye.

The therapeutic agent and prophylactic agent for each conjunctival disorder of the present invention can be administered parenterally. Examples of the dosage form include an eye drop, an ointment, and an injection. Of these, eye drops and eye drops are preferable, and eye drops are more preferable.

These can be formulated using techniques that are commonly used.

Examples of the eye drops include isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene stearate 40 and polyoxyethylene hardened castor oil, Stabilizers such as sodium citrate and sodium edetate, preservatives such as benzalkonium chloride and paraben, and the like can be used as needed. The pH may be within the range acceptable for ophthalmic preparations, but a range of 4 to 8 is preferred.

The ophthalmic solution can be prepared using a general-purpose base such as white petrolatum or liquid paraffin.

The therapeutic agent and prophylactic agent for each conjunctival disorder of the present invention is also useful as a prophylactic agent, but is preferably a therapeutic agent.

The dose of the therapeutic agent and prophylactic agent, in particular, the therapeutic agent for each conjunctival disorder of the present invention can be appropriately selected depending on the symptom, age, formulation and the like, but the concentration of the saccharin is 0.00001 to 1% (w / v) To 1% (w / v) may be administered one to several times per day, specifically, 1 to 6 times per day, preferably 2 to 3 times per day.

Example

Hereinafter, the results of Sakra's preparation examples, preparation examples and pharmacological tests will be shown, but these examples are for better understanding of the present invention and are not intended to limit the scope of the present invention.

[Preparation Example of Sacran]

The water-soluble pigment was removed by freezing, and then washed with water in an appropriate amount of freshwater cyanobacteria (Aphanothece sacrum). Then, the oil-soluble pigment was removed while stirring in ethanol for one day or night. Ethanol was separated from Suizenjinori from which the pigment was removed in this way, and then heated to 40 ° C in an aqueous sodium hydroxide solution of 0.4 to 0.6N and dissolved over about 5 hours while stirring. The aqueous solution of the sugar derivative extracted by this operation was neutralized with concentrated hydrochloric acid and desalted by immersing in 60 to 80% of isopropyl alcohol. After desalting, this concentrate was poured into 100% isopropanol while stirring to precipitate a gelatinous saccharin. The gelatin was dried with hot air at 85 ° C or more for 6 hours to obtain saccharin (present compound) derived from a fiber sugar derivative, Suizenganori.

[Formulation Example]

Representative examples of the preparation using saccharin (present compound) are shown below.

[Formulation Example 1] Eye drops

  In 100ml

    200 mg

900 mg of sodium chloride

Sterile purified water volume

[Formulation Example 2] Eye drops

  In 100ml

    200 mg

800 mg of sodium chloride

    100 mg of disodium hydrogen phosphate

    Sodium dihydrogenphosphate

    Sterile purified water volume

[Formulation Example 3] ophthalmic solution

  Of 100g

    0.2 g

    Liquid paraffin 10.0 g

    White petrolatum

[Pharmacological test]

1. Examination of healing efficacy of corneal disorders

A corneal disorder model was prepared according to the method of Fujihara et al. (Invest. Opthalmol. Vis. Sci 42 (1): 96-100 (2001)) using male SD rats. After corneal disorder modeling, the degree of corneal disorder was scored according to the method of Murakami et al. (New Ophthalmology 21 (1): 87-90. (2004)).

(Test Methods)

Male SD rats were anesthetized by general anesthesia with 2.5 mL / kg intraperitoneal injection of somnopentyl injection diluted 5-fold with physiological saline and anesthetized by inhalation of Escain (1.5%) did. Subsequently, the bilateral cancellous skin was dissected, the orbital lateral lacrimal gland was extracted and sealed with a Michel suture clamp. Thereafter, corneal disorders were induced over 8 weeks. In addition, a normal animal without the lacrimal gland extraction was prepared.

Next, 0.006% and 0.2% PBS solution of PBS (control) -containing compound was applied to normal eyes in both eyes (normal eye) for a phosphate buffer (PBS) and 5 μL of PBS solution I did not take 4 weeks.

The cornea was stained with fluorescein immediately before and 4 weeks after instillation. For each of the upper, middle, and lower portions of the cornea, the degree of staining by fluorescein was determined according to the following criteria, and the degree of corneal disorder was calculated from the average of the scores of the corners.

Tests were conducted in the same manner as described above to obtain the average value of the sum of the scores of the respective parts.

(Criteria)

1) As shown in Fig. 1, the cornea was divided into three parts, upper, middle, and lower, and a score of 0-3 was given based on the criteria in Table 1. 0.5 as a median value.

2) The scores of the three compartments were added together to obtain the disability score (0-9) in each observation.

[Table 1]

(result)

Table 2 shows the improvement ratios of the present compound points, which were calculated by the following calculation with the average value of the sum of the scores of the respective parts as a reference (improvement ratio: 0%) in the control group. The average value of the scores is an average of 8 eyes (4 eyes).

Improvement rate (%) = {(control) - (present compound)} / disorder x 100

Disability = {(control) - (normal)}

[Table 2]

(Review)

As is apparent from the results of the pharmacological tests using the above rats, the present compounds remarkably improve corneal disorders.

2. Healing efficacy test of corneal disorder (examination of number of eye drops)

Based on the above test results, the influence of the number of eye drops on the improvement effect of the corneal disorder of the 0.2% PBS solution of the present compound was examined by the same test method.

(Test Methods)

Male SD rats were subjected to the same procedure as described above to induce corneal disorders over 8 weeks. In addition, a normal animal without the lacrimal gland extraction was prepared.

Next, normal animals were administered with PBS (normal eye) in the eyes 6 times a day, PBS (control) in the corneal disorder model 6 times a day in the eyes, 0.2% PBS solution of the present compound twice daily in the eyes, 6 times, 5μL once each, not for 4 weeks.

The cornea was stained with fluorescein immediately before, 1 week, 2 weeks, and 4 weeks after the instillation, and the degree of corneal disorder was calculated in the same manner as the above test.

The test was conducted in the same manner as described above, and the average value of the scores of the respective parts was obtained.

(result)

Table 3 shows the improvement ratio of the compound of the present invention, which was obtained in the same manner as in the above test. The average value of the scores is an average of 8 eyes (4 eyes).

[Table 3]

(Review)

As is clear from the results of the pharmacological test using the rats described above, the present compound remarkably improved the corneal disorder and showed improvement effects even when it was administered twice a day, especially in the eyes of 6 times a day .

3. Evaluation test for improving the conjunctival epithelial disorder

On the basis of the above test results, the improvement effect on the conjunctival epithelial disorder (reduction of conjunctival epithelial cells) of the 0.2% PBS solution of the present compound was examined.

(Test Methods)

Male SD rats were subjected to the same procedure as described above to induce conjunctival epithelial disorders over 8 weeks. In addition, normal animals were prepared without lacrimal gland extraction.

Next, normal animals were administered with PBS (normal eye) in the eyes 6 times a day, PBS (control) in the conjunctival epithelium disorder model 6 times a day in the eyes, 0.2% PBS solution of the present compound twice daily And 6 times, 5 μL, respectively, for 4 weeks.

Four weeks after the onset of instillation, eyelids were extracted and histopathologically examined. The cut eyelashes were immersed and immersed in a 10% neutral buffered formalin solution, and after paraffin substitution, blocks were prepared with the side of the ear as the embedding surface and thinned to give a PAS reaction sample .

The number of conjunctival epithelial cells observed for each specimen was counted for each of the upper and lower eyelids using a lens with a magnification of 40 times.

(result)

Table 4 shows the effect of conjunctival goblet cell increase by the 4-week continuous point of the present compound. In addition, the average number of goblet cells is an average of 7 to 8 eyes (four goblets).

[Table 4]

(Review)

From the above histopathological test results, the present compound has the effect of improving the conjunctival epithelial disorder caused by the lacrimal gland excision and showed the improvement effect not only in the eye drops six times a day but also in the eye drops twice a day.

Claims (4)

A therapeutic agent or prophylactic agent for each conjunctival disorder containing saccharin. The method according to claim 1,
Each of which is selected from the group consisting of conjunctivitis, keratitis, conjunctivitis, and conjunctivitis. The method according to claim 1,
At least one therapeutic agent selected from the group consisting of dry eye, corneal ulcer, corneal erosion, corneal erosion, corneal epithelium defect, conjunctival epithelium defect, conjunctival epithelium disorder, dry keratoconjunctivitis, Or prophylaxis. 4. The method according to any one of claims 1 to 3,
A therapeutic agent or prophylactic agent which is a formulation of eye drops or ointments.

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